The prevalence of Type 2 diabetes has risen dramatically in the United States and globally and has now reached epidemic proportions (Olefsky and Glass, 2010). The etiology of this disease involves both insulin resistance and decreased beta cell insulin secretion, and one typically needs both defects (two hit hypothesis) in order to develop the hyperglycemic diabetic state (Defronzo, 2009; Olefsky and Glass, 2010; Weir and Bonner-Weir, 2004). Beta cell failure in type 2 diabetes is associated with at least 2 major mechanisms: reduced overall beta cell mass and decreased insulin secretory function per beta cell (Weir and Bonner-Weir, 2004). In the prediabetic, insulin resistant state, islets respond to the increased insulin demand with enhanced insulin secretion and increased beta cell mass to generate compensatory hyperinsulinemia and maintain relative euglycemia. However, when type 2 diabetes emerges, beta cell function and mass are significantly decreased, with insufficient insulin secretion to compensate for the insulin resistance, resulting in the chronic hyperglycemic diabetic state. This beta cell dysfunction is largely manifested as impaired glucose-stimulated insulin secretion (GSIS) and can be detected in the earliest stages of type 2 diabetes with complete loss of first phase GSIS (Defronzo, 2009; Weir and Bonner-Weir, 2004). On the other hand, decreased beta cell mass is usually not present at the time of diagnosis of type 2 diabetes (Rahier et al., 2008), suggesting that loss of beta cell mass is not responsible for the onset of type 2 diabetes, but rather is a consequence of diabetes.
Recently, it has been proposed that beta cell dysfunction in diabetes is associated with progressive dedifferentiation of beta cells (Jonas et al., 1999; Weir and Bonner-Weir, 2004). This is accompanied by reduced expression of genes necessary for maintaining the mature beta cell phenotype, including PDX-1, Glut2 and insulin, with increased expression of proliferative genes such as c-myc (Jonas et al., 1999; Rahier et al., 2008). This may provide a mechanism for increasing beta cell mass, at the expense of decreased beta cell function.
Fractalkine (also known as CX3CL1 or neurotactin; FKN) is the only member of the CX3C chemokine family, and is expressed in neurons, endothelial cells, hepatocytes and vascular smooth muscle cells (Aoyama et al., 2010; Cardona et al., 2006; Haskell et al., 1999; Lucas et al., 2001; Zernecke et al., 2008). FKN is produced as a membrane-bound protein, and mediates cell-to-cell adhesion and communication by binding to its cognate receptor CX3CR1 (also known as GPR13) (Combadiere et al., 2003; Imai et al., 1997; Lesnik et al., 2003; Tacke et al., 2007; Teupser et al., 2004; Zernecke et al., 2008). In liver, FKN expressed in hepatocyte and stellate cells is anti-fibrotic and can suppress inflammatory activation of Kupffer cells (Aoyama et al., 2010). In the brain, FKN mediates interactions between neurons and glial cells (Cardona et al., 2006). A soluble form of FKN is generated through proteolytic cleavage at the base of the mucin-like stalk, mediated by ADAM 10 and ADAM 17 (Garton et al., 2001; Hundhausen et al., 2003), producing an extracellular form of FKN which can regulate target cells by paracrine mechanisms. Furthermore, soluble FKN can exert paracrine effects in the extracellular space and can also enter the circulation to potentially cause endocrine effects on distant tissues (Shah et al., 2011).
CX3CR1 is the unique receptor for FKN and FKN is the only known ligand for this G protein-coupled receptor (Imai et al., 1997; Zernecke et al., 2008). FKN is expressed as a membrane-bound protein, which can interact with CX3CR1 on adjacent cells to facilitate cell:cell adhesion and communication, and plays a role in the attachment of monocytes/macrophages to CX3CR1 expressing cell types (Haskell et al., 1999; Zernecke et al., 2008).
It has recently been reported that two single nucleotide polymorphisms (T280M and V249I), located in the coding sequence of human CX3CR1, are associated with an increased incidence of type 2 diabetes and metabolic syndrome (Shah et al., 2011; Sirois-Gagnon et al., 2011). These CX3CR1 gene variants result in lower FKN binding affinity, consistent with the view that the FKN/CX3CR1 system plays a beneficial role in the maintenance of proper insulin secretion and glycemic control. On the other hand, circulating levels of soluble FKN are not decreased in type 2 diabetic patients and, in fact, are slightly higher than controls (Shah et al., 2011).